Gene-Environment Interactions for Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures in the 23andMe, Inc. research dataset. METHODS: Using a validated PD polygenic risk score and common PD-associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and 7 lifestyle and environmental factors: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA). RESULTS: We observed that T2D, as well as higher BMI, caffeine consumption, and tobacco use, were associated with lower odds of PD, whereas head injury, pesticide exposure, GBA carrier status, and PD polygenic risk score were associated with higher odds. No significant association was observed between PA and PD. In interaction analyses, we found statistical evidence for an interaction between polygenic risk of PD and the following environmental/lifestyle factors: T2D (p = 6.502 × 10-8), PA (p = 8.745 × 10-5), BMI (p = 4.314 × 10-4), and tobacco use (p = 2.236 × 10-3). Although BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D, as well as PD and PA, varied depending on polygenic risk score. INTERPRETATION: We provide preliminary evidence that associations between some environmental and lifestyle factors and PD may be modified by genotype. ANN NEUROL 2024;95:677-687.

Neuroanatomical and prognostic associations of depression in Parkinson's disease.

BACKGROUND: Depression is reported as a risk factor, prodromal feature and late consequence of Parkinson's disease (PD). We aimed to evaluate the timing, neuroanatomy and prognostic implications of depression in PD. METHODS: We used data from 434 023 participants from UK Biobank with 14.1 years of follow-up. Multivariable regression models established associations of depression with incident PD and regional brain volumes. Cox proportional hazards models assessed prognostic associations of depression in PD with incident dementia and all-cause mortality. RESULTS: Of 2632 individuals with incident PD, 539 (20.5%) were diagnosed with depression at some point. Depression was associated with an increased risk of subsequent PD (risk ratio 1.53, 95% CI 1.37 to 1.72). Among incident PD cases, depression prevalence rose progressively from 10 years pre-PD diagnosis (OR 2.10, 95% CI 1.57 to 2.83) to 10 years postdiagnosis (OR 3.51, 95% CI 1.33 to 9.22). Depression severity in PD was associated with reduced grey matter volume in structures including the thalamus and amygdala. Depression prior to PD diagnosis increased risk of dementia (HR 1.47, 95% CI 1.05 to 2.07) and mortality (HR 1.30, 95% CI 1.07 to 1.58). CONCLUSIONS: This large-scale prospective study demonstrated that depression prevalence increases from 10 years before PD diagnosis and is a marker of cortical and subcortical volume loss. Depression before PD diagnosis signals a worse prognosis in terms of dementia and mortality. This has clinical implications in stratifying people with poorer cognitive and prognostic trajectory in PD.

Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease.

OBJECTIVES: Patients with established Parkinson's disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis. METHODS: We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations. RESULTS: After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1-SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07-1.32, padjusted = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C-reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; ORMR = 1.09, 95% CI = 1.01-1.18, p = 0.02). INTERPRETATION: We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD. ANN NEUROL 2021;89:803-812.

Parkinson's disease determinants, prediction and gene-environment interactions in the UK Biobank.

OBJECTIVE: To systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson's disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores. METHODS: We identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene-environment interactions and compare predictive models for PD. RESULTS: Strong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes. INTERPRETATION: Here, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene-environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom.

BACKGROUND: Epstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ~ 95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future. METHODS: We conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. RESULTS: 1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10-15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking. CONCLUSIONS: We report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.

Cladribine: mechanisms and mysteries in multiple sclerosis.

OBJECTIVES: The aims of this manuscript were to review the evidence for the efficacy and safety of cladribine in multiple sclerosis (MS) and to review the molecular and cellular mechanisms by which cladribine acts as a disease-modifying therapy in MS. METHODS: This is a narrative review of the available clinical and preclinical data on the use of cladribine in MS. RESULTS: Clinical trial data argue strongly that cladribine is a safe and effective therapy for relapsing MS and that it may also be beneficial in progressive MS. The pharmacology of cladribine explains how it is selectively toxic towards lymphocytes. Immunophenotyping studies show that cladribine depletes lymphocyte populations in vivo with a predilection for B cells. In vitro studies demonstrate that cladribine also exerts immunomodulatory influences over innate and adaptive immunity. CONCLUSIONS: Cladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine's action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.

Is there a moral obligation to select healthy children?

Reproductive decision-making in the post-genetic age is a minefield of complex ethical problems. One such problem centres on whether there is an obligation on reproducers to choose the best possible child. This paper focusses on a simplified scenario: there are two embryos to choose from, one of which will develop a condition that diminishes quality of life but would still have 'a life worth living', the other of which is normal. Is there an obligation to choose the healthier child? If so, what is the nature and scope of this obligation? The answer to these questions relies on a satisfactory answer to the non-identity problem (NIP). This paper explores several solutions to the NIP and argues for a solution grounded in the concept of harm. Various accounts of harm are discussed and synthesised to provide a new 'comparative bad state view' of harm. This account is used to justify the obligation to choose the healthier child. How far should this obligation go? This paper rejects the conservative position of 'procreative autonomy' - which holds that such obligations have no place in reproductive decisions - and the radical position of 'procreative beneficence' - which holds that there is an even stronger obligation to make the best possible child. The obligation to choose the healthier child may be over-ridden by countervailing reasons; the moral calculus in any individual case will be largely dependent on the expected quality of life of the child.

Vitamin D genetic risk scores in multiple sclerosis.

BACKGROUND: Low serum 25(OH)D3 (vD) is an environmental risk factor for multiple sclerosis (MS). Lower vD levels during early disease may be associated with long-term disability. Determinants of serum vD levels in healthy individuals include supplementation behaviour and genetic factors. These determinants have been less well studied in people with MS (pwMS). METHODS: We developed a vD-weighted genetic risk score (GRS) and validated this in 373,357 UK Biobank participants without MS. We measured serum 25(OH)D3 and genotyped six vD-associated SNPs (rs12785878, rs10741657, rs17216707, rs10745742, rs8018720, rs2282679) in a cohort of pwMS (n = 315) with age and geographically matched controls (n = 232). We then assessed predictors of serum vD concentration in this cohort. RESULTS: The GRS was strongly associated with vD status in the Biobank cohort (p < 2 × 10-16). vD supplementation, having MS, lower BMI, increased age and supplementation dose were associated with higher vD levels (false discovery rate, FDR < 5%). In multivariable models adjusting for supplementation, BMI, age, sex, and MS status, the GRS was strongly associated with vD level (p = 0.004), but not in those who supplemented (p = 0.47). CONCLUSIONS: Our findings suggest that vD supplementation is the major determinant of vD level in pwMS, with genetic determinants playing a far smaller role.

Towards a global view of multiple sclerosis genetics.

Multiple sclerosis (MS) is a neuroimmunological disorder of the CNS with a strong heritable component. The genetic architecture of MS susceptibility is well understood in populations of European ancestry. However, the extent to which this architecture explains MS susceptibility in populations of non-European ancestry remains unclear. In this Perspective article, we outline the scientific arguments for studying MS genetics in ancestrally diverse populations. We argue that this approach is likely to yield insights that could benefit individuals with MS from all ancestral groups. We explore the logistical and theoretical challenges that have held back this field to date and conclude that, despite these challenges, inclusion of participants of non-European ancestry in MS genetics studies will ultimately be of value to all patients with MS worldwide.

Predicting Multiple Sclerosis: Challenges and Opportunities.

Determining effective means of preventing Multiple Sclerosis (MS) relies on testing preventive strategies in trial populations. However, because of the low incidence of MS, demonstrating that a preventive measure has benefit requires either very large trial populations or an enriched population with a higher disease incidence. Risk scores which incorporate genetic and environmental data could be used, in principle, to identify high-risk individuals for enrolment in preventive trials. Here we discuss the concepts of developing predictive scores for identifying individuals at high risk of MS. We discuss the empirical efforts to do so using real cohorts, and some of the challenges-both theoretical and practical-limiting this work. We argue that such scores could offer a means of risk stratification for preventive trial design, but are unlikely to ever constitute a clinically-helpful approach to predicting MS for an individual.

Gene-Environment Interactions in Multiple Sclerosis: A UK Biobank Study.

OBJECTIVE: We sought to determine whether genetic risk modifies the effect of environmental risk factors for multiple sclerosis (MS). To test this hypothesis, we tested for statistical interaction between polygenic risk scores (PRS) capturing genetic susceptibility to MS and environmental risk factors for MS in UK Biobank. METHODS: People with MS were identified within UK Biobank using ICD-10-coded MS or self-report. Associations between environmental risk factors and MS risk were quantified with a case-control design using multivariable logistic regression. PRS were derived using the clumping-and-thresholding approach with external weights from the largest genome-wide association study of MS. Separate scores were created including major histocompatibility complex (MHC) (PRSMHC) and excluding (PRSnon-MHC) the MHC locus. The best-performing PRS were identified in 30% of the cohort and validated in the remaining 70%. Interaction between environmental and genetic risk factors was quantified using the attributable proportion due to interaction (AP) and multiplicative interaction. RESULTS: Data were available for 2,250 people with MS and 486,000 controls. Childhood obesity, earlier age at menarche, and smoking were associated with MS. The optimal PRS were strongly associated with MS in the validation cohort (PRSMHC: Nagelkerke's pseudo-R2 0.033, p = 3.92 × 10-111; PRSnon-MHC: Nagelkerke's pseudo-R2 0.013, p = 3.73 × 10-43). There was strong evidence of interaction between polygenic risk for MS and childhood obesity (PRSMHC: AP = 0.17, 95% CI 0.06-0.25, p = 0.004; PRSnon-MHC: AP = 0.17, 95% CI 0.06-0.27, p = 0.006). CONCLUSIONS: This study provides novel evidence for an interaction between childhood obesity and a high burden of autosomal genetic risk. These findings may have significant implications for our understanding of MS biology and inform targeted prevention strategies.

Evaluation of remote assessments for multiple sclerosis in an in-home setting.

BACKGROUND: There is an urgent clinical need for reliable remote monitoring methods in Multiple Sclerosis (MS). We evaluated the use of remotely patient-recorded timed 25-foot walk (rT25FW) and nine-hole peg test (r9HPT). METHODS: Seventy-one people with MS completed a previously-validated online EDSS (webEDSS) and r9HPT, and 108 completed the webEDSS and rT25FW. RESULTS: There was a mild-moderate positive correlation between webEDSS and rT25FW, and no significant correlation between webEDSS and r9HPT. Distributions of rT25FW and r9HPT times were positively skewed. CONCLUSIONS: Our results provide pilot evidence that remote monitoring of MS is potentially valid but requires refinement before wide-scale implementation. With a median EDSS of 4.5 and EDSS range of 0 - 8.0, at least some patients with ambulatory difficulty are able to complete the assessments.

Remote testing of vitamin D levels across the UK MS population-A case control study.

OBJECTIVE: The association between vitamin D deficiency and multiple sclerosis (MS) is well described. We set out to use remote sampling to ascertain vitamin D status and vitamin D supplementation in a cross-sectional study of people with MS across the UK. METHODS: People with MS and matched controls were recruited from across the UK. 1768 people with MS enrolled in the study; remote sampling kits were distributed to a subgroup. Dried blood spots (DBS) were used to assess serum 25(OH)D in people with MS and controls. RESULTS: 1768 MS participants completed the questionnaire; 388 MS participants and 309 controls provided biological samples. Serum 25(OH)D was higher in MS than controls (median 71nmol/L vs 49nmol/L). A higher proportion of MS participants than controls supplemented (72% vs 26%, p<0.001); people with MS supplemented at higher vD doses than controls (median 1600 vs 600 IU/day, p<0.001). People with MS who did not supplement had lower serum 25(OH)D levels than non-supplementing controls (median 38 nmol/L vs 44 nmol/L). Participants engaged well with remote sampling. CONCLUSIONS: The UK MS population have higher serum 25(OH)D than controls, mainly as a result of vitamin D supplementation. Remote sampling is a feasible way of carrying out large studies.

A dangerous method? The use of induced pluripotent stem cells as a model for schizophrenia.

Schizophrenia is a devastating and prevalent psychiatric illness. Progress in understanding the basic pathophysiological processes underlying this disorder has been hindered by the lack of appropriate models. With the advent of induced pluripotent stem cell (iPSC) technology, it is now possible to generate live neurons in vitro from somatic tissue of schizophrenia patients. Despite its several limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia. The phenotypic insights garnered with iPSC models of schizophrenia include transcriptional dysregulation, oxidative stress synaptic dysregulation, and neurodevelopmental abnormalities. Potential pitfalls of this work include the possibility of introducing random genetic mutations during the reprogramming process, the inadequacy of using neurons from other patients as controls, the inability to capture the complex environmental contribution to schizophrenia pathogenesis, the difficulty in modelling neurodevelopment, and the difficulty in modelling the interaction of multiple neuronal and non-neuronal cell types. However, with the increasing sophistication of available reprogramming techniques, co-culture technology, and gene correction strategies, iPSC-derived neurons will continue to elucidate how neuronal function is disrupted in schizophrenia.

Stemming the hype: what can we learn from iPSC models of Parkinson's disease and how can we learn it?

Parkinson's disease (PD) is a prevalent and debilitating neurodegenerative disorder for which there are no available cures. PD pathogenesis is poorly understood because appropriate animal and in vitro models are lacking. The development of induced Pluripotent Stem Cells (iPSCs) has allowed researchers to generate disease-specific dopaminergic neurons in vitro by reprogramming skin cells from patients with the disease. It is hoped that this unprecedented access to PD patients' neurons will yield mechanistic insights into PD pathogenesis, a platform for drug screening, and a means of early diagnosis. In this article I critically evaluate the current usage of iPSCs in PD research. I first outline the iPSC paradigm and emphasise the benefits of this approach for modelling PD. I then ask what we can learn from the iPSC-based studies done to date. I argue that these studies have not been particularly informative when considered as an isolated body of evidence. I suggest that the limitations of this technology can be overcome, and I conclude that iPSCs have the potential to be an extremely useful tool in PD research. However, they will never be a panacea and should continue to be used in concert with other in vitro and animal models.